基于FXR?FGF19通路研究益生菌對膽總管結石患者膽汁酸代謝的影響

背景：膽總管結石在取石術后有較高的復發率。近年研究表明腸道微生態失衡與膽固醇結石的形成有關。目的：探究益生菌干預對膽固醇結石高危人群血清脂多糖（LPS）以及膽汁酸代謝指標的影響。方法：選取2021年6月—2023年6月在石河子大學第一附屬醫院行ERCP取石術的膽總管結石患者60例，收集膽汁和糞便樣本行細菌培養。將患者隨機分為對照組和益生菌干預組，對照組取石術后予常規支持治療，干預組在常規治療的基礎上服用雙歧桿菌三聯活菌腸溶膠囊420 mg，每日2次，連續6個月。檢測治療前后革蘭陰性菌細胞壁成分LPS、膽汁酸代謝關鍵分子成纖維細胞生長因子19（FGF19）和膽汁酸合成限速酶膽固醇7α?羥化酶（CYP7A1）血清水平的變化。結果：膽總管結石患者膽汁、糞便細菌培養顯示主要致病菌為大腸埃希菌和肺炎克雷伯菌。ERCP取石術后6個月，患者血清LPS、FGF19水平明顯降低，CYP7A1水平明顯升高（P均lt;0.05），益生菌干預組數據變化較對照組更為顯著（P均lt;0.05）。結論：口服益生菌制劑可降低膽固醇結石高危人群的血清LPS水平，同時調節膽汁酸經腸肝循環代謝的經典通路法尼酯X受體（FXR）?FGF19通路，從而減少膽汁中的膽固醇過飽和，降低膽固醇結石的形成概率。

關鍵詞 益生菌； 脂多糖類； 膽總管結石； 膽汁酸代謝； 法尼酯X受體； 膽固醇7?α?羥化酶

Effect of Probiotics on Bile Acid Metabolism via FXR?FGF19 Pathway in Patients With Choledocholithiasis YE Lüwang1， WANG Cong1， FAN Junwei1， JIANG Ting1， DU Mengyan1， CHEN Weigang2， LIU Fang2. 1Shihezi University School of Medicine， Shihezi， Xinjiang Uygur Autonomous Region （832002）; 2Department of Gastroenterology， the First Affiliated Hospital of Shihezi University， Shihezi， Xinjiang Uygur Autonomous Region

Correspondence to： LIU Fang， Email： 18009935806@163.com

Background： Recurrence after stone removal is common in patients with choledocholithiasis. Recent studies have indicated that dysbiosis in gut microbiota plays an important role in the formation of cholesterol gallstones. Aims： To explore the effect of probiotics supplementation on serum lipopolysaccharide （LPS） and the indicators of bile acid metabolism in patients with a high risk of cholesterol gallstone formation. Methods： Sixty choledocholithiasis patients undergoing ERCP lithotomy were recruited at the First Affiliated Hospital of Shihezi University from June 2021 to June 2023. Bile and stool samples were collected for bacterial culture. Then the patients were randomly allocated into two groups：" patients in control group received conventional supportive therapy after calculus removal， while those in probiotics intervention group were given oral bifid triple viable enteric capsule 420 mg， twice a day for 6 months based on conventional therapy. Changes in serum levels of LPS， the cell wall component of Gram?negative bacteria， fibroblast growth factor 19 （FGF19）， the key molecule in bile acid metabolism， and cholesterol 7α?hydroxylase （CYP7A1）， the rate?limiting enzyme of bile acid synthesis， were determined and compared between the two groups. Results： Escherichia coli and Klebsiella pneumoniae were the main pathogens in bile and stool of patients with choledocholithiasis. Six months after ERCP lithotomy， the serum levels of LPS and FGF19 were decreased， and the serum level of CYP7A1 was increased in both groups （all Plt;0.05）， especially in probiotics intervention group （all Plt;0.05）. Conclusions： Oral probiotics supplementation can reduce the serum LPS level and modulate the canonical pathway of enterohepatic circulation of bile acids ?? farnesoid X receptor （FXR）?FGF19 pathway in high?risk patients of cholesterol gallstone formation. These alterations reduce the cholesterol supersaturation in bile and inhibit the probability of cholesterol gallstone formation.

Key words Probiotics; Lipopolysaccharides; Choledocholithiasis; Bile Acid Metabolism; Farnesoid X Receptor; Cholesterol 7?alpha?Hydroxylase

膽石癥在全球范圍內十分普遍，我國報道的成人膽囊結石患病率為2.3%～6.5%，其中70%以上為膽固醇結石[1]。膽總管結石多繼發于膽囊結石，結石系從膽囊脫落至膽總管，內鏡取石術后復發率高達12.4%[2]，且通常會誘發急性膽管炎、急性膽源性胰腺炎，該類患者也是膽固醇結石再次形成的高危人群。……